First-In-Class CD13-Targeted Tissue Factor tTF-NGR in Patients with Recurrent or Refractory Malignant Tumors: Results of a Phase I Dose-Escalation Study

Abstract

Background: Aminopeptidase N (CD13) is present on tumor vasculature cells and some tumor cells. Truncated tissue factor (tTF) with a C-terminal NGR-peptide (tTF-NGR) binds to CD13 and causes tumor vascular thrombosis with infarction. Methods: We treated 17 patients with advanced cancer beyond standard therapies in a phase I study with tTF-NGR (1-h infusion, central venous access, 5 consecutive days, and rest periods of 2 weeks). The study allowed intraindividual dose escalations between cycles and established Maximum Tolerated Dose (MTD) and Dose-Limiting Toxicity (DLT) by verification cohorts. Results: MTD was 3 mg/m2 tTF-NGR/day × 5, q day 22. DLT was an isolated and reversible elevation of high sensitivity (hs) Troponin T hs without clinical sequelae. Three thromboembolic events (grade 2), tTF-NGR-related besides other relevant risk factors, were reversible upon anticoagulation. Imaging by contrast-enhanced ultrasound (CEUS) and dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) showed major tumor-specific reduction of blood flow in all measurable lesions as proof of principle for the mode of action of tTF-NGR. There were no responses as defined by Response Evaluation Criteria in Solid Tumors (RECIST), although some lesions showed intratumoral hemorrhage and necrosis after tTF-NGR application. Pharmacokinetic analysis showed a t1/2(terminal) of 8 to 9 h without accumulation in daily administrations. Conclusion: tTF-NGR is safely applicable with this regimen. Imaging showed selective reduction of tumor blood flow and intratumoral hemorrhage and necrosis.

Platelets, Constant and Cooperative Companions of Sessile and Disseminating Tumor Cells, Crucially Contribute to the Tumor Microenvironment

“…Instead of inhibiting TF, another therapeutic approach utilizes TF to pharmaceutically induce tumor infarction. To this end, recombinant TF is directed to tumor vessels either in a soluble form or bound to nanoparticles (Schwöppe et al, 2010;Ding et al, 2013;Schliemann et al, 2020). By enriching TF in the tumor vessels, an excessive fibrin deposition and thrombus formation occlude the tumor vasculature (Jahanban-Esfahlan et al, 2017).…”

“…By enriching TF in the tumor vessels, an excessive fibrin deposition and thrombus formation occlude the tumor vasculature (Jahanban-Esfahlan et al, 2017). The resulting hemostatic plug abolishes the blood flow and the nutrient support for the tumor, resulting in tumor infarction and regression of tumor tissue (Schliemann et al, 2020).…”

Targeting Tissue Factor to Tumor Vasculature to Induce Tumor Infarction

“…tTF-NGR has recently been investigated in a first-in-class phase I study, which recruited a total of 17 patients suffering from a variety of different solid tumor entities with previously exhausted standard therapy [ 87 , 88 ]. The study protocol was approved by the Ethical Board of the Physicians’ Chamber of Westphalia-Lippe and the Westphalian Wilhelms University of Muenster, Germany (AZ 2016-414-f-A) and by the Paul Ehrlich Institute (PEI), Langen, Germany.…”

“…The safety profile in phase I with tTF-NGR compares favorably to a variety of other anticancer drugs. In particular, the increase of Troponin T hs potentially is a sensitive and early biomarker for safety [ 88 ]. Furthermore, the thromboembolic events observed at higher doses were only grade II and completely reversible upon drug withdrawal and anticoagulation, these kinds of specific and prompt countermeasures not always being available for other drugs approved for clinical use in oncology.…”

“…Middle panels for ( A , B ) ( m ): CEUS arbitrary units (a.u.) for the wash-in perfusion index (WIAUC/RT; for the methodological details see [ 88 ]) representing the contrast flow through the vasculature of the lesion. For color representation of the 3 different ROI measured, see upper panel.…”